domatinostat tosylate

Description: Domatinostat (formerly known as 4SC-202) is a novel class I HDAC inhibitor (HDACi) that potently inhibited survival and proliferation of primary human colon cancer cells and established CRC lines (HT-29, HCT-116, HT-15, and DLD-1). It has IC50 values of 1.20 uM, 1.12 uM, and 0.57 uM for HDAC1, HDAC2, and HDAC3, respectively. Domatinostat also displays inhibitory activity against Lysine specific demethylase 1 (LSD1). 4SC-202 provoked apoptosis activation in CRC cells, while caspase inhibitors (z-VAD-CHO and z-DVED-CHO) significantly alleviated 4SC-202-exerted cytotoxicity in CRC cells. Meanwhile, 4SC-202 induced dramatic G2-M arrest in CRC cells. Further studies showed that AKT activation might be an important resistance factor of 4SC-202. 4SC-202-induced cytotoxicity was dramatically potentiated with serum starvation, AKT inhibition (by perifosine or MK-2206), or AKT1-shRNA knockdown in CRC cells. On the other hand, exogenous expression of constitutively active AKT1 (CA-AKT1) decreased the sensitivity by 4SC-202 in HT-29 cells. Notably, 4SC-202, at a low concentration, enhanced oxaliplatin-induced in vitro anti-CRC activity. In vivo, we showed that oral gavage of 4SC-202 inhibited HT-29 xenograft growth in nude mice, and when combined with oxaliplatin, its activity was further strengthened. Together, these pre-clinical results indicate that 4SC-202 may be further investigated as a valuable anti-CRC agent/chemo-adjuvant.

References: Tumour Biol. 2016 Aug; 37(8):10257-67; Target Oncol. 2016 Dec; 11(6):783-798.

Related CAS#:910462-43-0 (free)